JPS6247176B2 - - Google Patents

Info

Publication number
JPS6247176B2
JPS6247176B2 JP54117771A JP11777179A JPS6247176B2 JP S6247176 B2 JPS6247176 B2 JP S6247176B2 JP 54117771 A JP54117771 A JP 54117771A JP 11777179 A JP11777179 A JP 11777179A JP S6247176 B2 JPS6247176 B2 JP S6247176B2
Authority
JP
Japan
Prior art keywords
group
reaction
acid
mmol
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
JP54117771A
Other languages
Japanese (ja)
Other versions
JPS5640651A (en
Inventor
Shinji Terao
Mitsuru Shiraishi
Kaneyoshi Kato
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
Original Assignee
Takeda Chemical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries Ltd filed Critical Takeda Chemical Industries Ltd
Priority to JP11777179A priority Critical patent/JPS5640651A/en
Priority to US06/182,401 priority patent/US4388312A/en
Priority to DE8080303172T priority patent/DE3061226D1/en
Priority to EP80303172A priority patent/EP0025692B1/en
Priority to CA000360089A priority patent/CA1173028A/en
Publication of JPS5640651A publication Critical patent/JPS5640651A/en
Priority to US06/471,457 priority patent/US4533554A/en
Publication of JPS6247176B2 publication Critical patent/JPS6247176B2/ja
Granted legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/30—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C07C243/32—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C66/00—Quinone carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/32—Nitrogen atoms acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biochemistry (AREA)
  • Cardiology (AREA)
  • Pulmonology (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Pain & Pain Management (AREA)
  • Biotechnology (AREA)
  • Immunology (AREA)
  • Neurosurgery (AREA)
  • Rheumatology (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Saccharide Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

【発明の詳細な説明】[Detailed description of the invention]

本発明は医薬またはその中間体として有用な新
規キノン化合物およびその製造法に関する。 ビタミンＥ、ビタミンＫおよびユビキノンなど
の脂溶性ビタミン類は一般に生体膜、特にリン脂
質層内においてそれぞれの化合物群に特有のビタ
ミンもしくはビタミン様作用を発現する。本発明
者らはこれらの化合物のポリプレニル側鎖の末端
をアミド化した化合物群が優れた生理活性を有す
ることを見出し、これに基づいて本発明を完成し
た。 すなわち、本発明の化合物は一般式 〔式中、ｎは１から10までの整数を、R1はメチル
基、メトキシ基または２つのR1で−CH＝CH−
CH＝CH−基を示し、R2は(1)アミノ、(2)モノま
たはジC1-6アルキルアミノ、(3)フエニル−C1-3ア
ルキルアミノ、(4)ピリジル−C1-3アルキルアミ
ノ、(5)C1-4アルコキシアミノ、(6)ヒドロキシアニ
リノ、(7)ｍ−トリフロロメチルフエニルヒドラジ
ノ、(8)Ｎ・Ｎ−ジメチルヒドラジノ、(9)ヒスタミ
ノ、(10)４−メチル−１−ピペラジニルアミノ、(11)
１−メチル−４−ピペリジニルアミノ、(12)５−
（1H−テトラゾリル）アミノ、（13）ピロリジニ
ル、（14）プレニル、ポリプレニル、トリメトキ
シベンジルまたはメチレンジオキシベンジルで置
換されたピペラジニル、（15）ピペリジノ、（16）
モルホリノまたは（17）エピネフリン、ノルエピ
ネフリン、グリシン、フエニルグリシン、メチオ
ニンまたはβ−シトシンアラビノサイドのアミノ
残基を示す〕で表わされるキノン化合物およびそ
のヒドロキノン体である。 上記キノン化合物（ａ）のヒドロキノン体は
一般式 〔式中、ｎ、R1およびR2は前記と同意義、R3は水
素原子または保護基を示す〕で表わされる。 上記（ａ）および（ｂ）に関し、R2で示
されるモノまたはジC1-6アルキルアミノ基として
はたとえばメチルアミノ、エチルアミノ、プロピ
ルアミノ、イソプロピルアミノ、ブチルアミノ、
イソブチルアミノ、sec−ブチルアミノ、tert−
ブチルアミノ、ペンチルアミノ、ヘキシルアミ
ノ、ジメチルアミノ、ジエチルアミノ、メチルエ
チルアミノ基などが、フエニル−C1-3アルキルア
ミノ基としてはたとえばベンジルアミノ、フエネ
チルアミノ、α−メチルベンジルアミノ基など
が、ピリジル−C1-3アルキルアミノ基としてはた
とえば２−ピリジルメチルアミノ、３−ピリジル
メチルアミノ、４−ピリジルエチルアミノ基など
が、C1-4アルコキシアミノ基としてはたとえばメ
トキシアミノ、エトキシアミノ基などが、プレニ
ルまたはポリプレニル基で置換されたピペラジニ
ルとしてはたとえばプレニルピペラジニル、ゲラ
ニルピペラジニル、フアルネシルピペラジニル、
ネリルピペラジニル、ソラネシルピペラジニル、
ゲラニルゲラニルピペラジニルなどが、トリメト
キシベンジルで置換されたピペラジニルとしては
たとえば４−（３・４・５−トリメトキシベンジ
ル）ピペラジニル基などが、またメチレンジオキ
シベンジルで置換されたピペラジニルとしてはた
とえば４−（３・４−メチレンジオキシベンジ
ル）ピペラジニルなどがそれぞれあげられる。
R2で示されるエピネフリン、ノルエピネフリ
ン、グリシン、メチオニンまたはβ−シトシンア
ラビノサイドのアミノ残基はこれらのアミノ基に
結合する水素１個を除いた基を意味する。 前記式（ｂ）に関し、R3で示される保護基
としては通常水酸基の保護に用いられる基、たと
えばC1-3アルキル基（例、メチル基）、C1-3アル
コキシメチル基（例、メトキシメチル基）、C2-4
アルカノイル基（例、アセチル基）、ベンジル
基、テトラヒドロピラニル基、テトラヒドロフラ
ニル基などがあげられる。 本発明化合物（ａ）および（ｂ）は、たと
えば一般式 または 〔式中、ｎは１から10までの整数を、R1はメチル
基、メトキシ基または２つのR1で−CH＝CH−
CH＝CH−基を示し、R3は保護基を示す〕で表
わされるカルボン酸またはそのカルボキシル基に
おける反応性誘導体に一般式 R2−Ｈ （） 〔式中、R2は置換されていてもよいアミノ基を示
す〕で表わされる化合物を反応させてアミド化す
ることにより製造し得る。 カルボン酸（ａ）または（ｂ）と化合物
（）との反応は、通常適当な活性縮合剤の存在
下に行われ、かかる縮合剤としては、Ｎ・N′−
ジシクロヘキシルカルボジイミド（DCC）、Ｎ−
ヒドロキシベンゾトリアゾールとDCC、Ｎ−ヒ
ドロキシコハク酸イミドとDCC、２−チアゾリ
ン−２−チオールとDCC、ｐ−ニトロフエノー
ルとDCC、クロル炭酸エステルとトリエチルア
ミンなどが用いられる。縮合剤の使用量は、通常
（ａ）または（ｂ）に対して約１〜２当量程
度である。 反応は、通常適当な有機溶媒（例、ジクロルメ
タン、テトラヒドロフラン、アセトニトリル、ジ
メチルアセトアミド、ジメチルホルムアミド、
１・２−ジメトキシエタン）中、約−20℃〜150
℃程度の反応温度で行われる。 カルボン酸（ａ）または（ｂ）の反応性誘
導体としては、たとえば酸クロライド、混合酸無
水物、活性エステル、活性アミドなどがあげら
れ、これらは自体公知の方法、たとえば酸クロラ
イドはカルボン酸（ａ）または（ｂ）を五塩
化リン、蓚酸クロライド、チオニルクロライド、
四塩化炭素−トリフエニルホスフイン、ホスゲン
などとの反応によつて得ることができる。アミド
化反応は通常繁用される合成反応条件、たとえば
有機塩基（例、トリエチルアミン、ピリジンな
ど）または無機塩基（例、炭酸ナトリウム、炭酸
カリウムなど）の存在下で酸クロライド（ａ）
または（ｂ）と（）とを反応させることによ
つて行われる。 かくして製造されるキノン化合物（ａ）およ
びそのヒドロキノン体（ｂ）は、自体公知の分
離精製手段（例、クロマトグラフイー、結晶化）
などにより単離採取することができる。なお、
（ａ）と（ｂ）は自体公知の反応により相互
変換し得る。たとえば保護された（ｂ）から
（ａ）へ導くには、（ｂ）を自体公知の保護基
除去反応（例、酸性加水分解、アルカリ性加水分
解など）、ついで酸化反応（例、空気酸化、塩化
第二鉄酸化）に付すか、または（ｂ）を酸化的
脱メチル化反応（例、酸化銀による反応）に付す
ことにより、また逆に（ａ）から（ｂ）へは
還元（例、水素化ホウ素ナトリウムまたはチオ硫
酸ナトリウムによる還元）および必要に応じ保護
基導入反応（例、エーテル化、ベンジル化、アシ
ル化）に付すことにより、それぞれ目的を達する
ことができる。 化合物（ａ）および（ｂ）は、そのR2基
中にたとえばピペラジン、ピリジン骨格等に由来
する塩基性窒素機能団が存在する場合には酸付加
塩を形成していてもよく、かかる塩としては、有
機酸（例、酢酸、マロン酸、フマール酸、マレイ
ン酸、コハク酸、蓚酸、クエン酸、酒石酸）塩や
無機酸（例、塩酸、リン酸、硫酸、硝酸）塩があ
げられる。また（ａ）および（ｂ）のR2基
中にたとえばアミノ酸由来のカルボキシル基等が
存在する場合にはアルカリ金属（例、リチウム、
ナトリウム、カリウム）塩を形成していてもよ
い。これらの塩類も当然本発明化合物の範囲に包
含されるものである。 本発明化合物（ａ）および（ｂ）は、プロ
スタグランジン生合成の調節作用（プロスタグラ
ンジンE2、I2作用増強など）、抗SRS−Ａ（Slow
reacting substance of anaphylaxis）作用やア
ドレナリン様作用遮断効果を有し、動物とりわけ
哺乳動物（例、ラツト、マウス、モルモツト、イ
ヌ、ウサギ、ヒト）に対して血圧降下、鎮痛、抗
潰瘍、抗炎症、利尿、免疫調整、抗喘息、抗アレ
ルギー、血小板凝集阻止、脳循環改善作用などの
生理作用を示し、たとえば降圧剤、鎮痛剤、抗潰
瘍剤、抗炎症剤、利尿剤、免疫調整剤、抗喘息
剤、抗アレルギー剤、抗血栓剤、脳循環改善剤な
どの医薬として、たとえば高血圧症、脳血栓症、
虚血性心筋梗塞、冠状血管障害、プロスタグラン
ジンおよびトロンボキサン生合成調節機構失調
症、免疫不全、気管支喘息、アレルギー症などの
治療または予防に有用である。 本発明化合物は毒性が低く、そのままもしくは
自体公知の薬学的に許容されうる担体、賦形剤な
どと混合した医薬組成物〔例、錠剤、カプセル剤
（ソフトカプセル、マイクロカプセルを含む）、液
剤、注射剤、坐剤〕として経口的もしくは非経口
的に安全に投与することができる。投与量は投与
対象、投与ルート、症状などによつても異なる
が、たとえば成人の高血圧症または気管支喘息に
対して経口投与する場合、通常１回量として約
0.2mg／Kg〜25mg／Kg体重程度、好ましくは約0.5
〜10mg／Kg体重程度を１日１〜３回程度投与する
のが好都合である。 本発明の方法において原料化合物として用いる
化合物（ａ）および（ｂ）は、たとえば特開
昭53−50123号公報、特開昭54−76507号公報、特
開昭55−153739号公報、ザ・ジヤーナル・オフ・
オーガニツク・ケミストリー（The Journal of
Organic Chemistry）、第44巻、868頁（1979年）
およびシンセシス（synthesis）、467頁（1979
年）などに記載された方法またはこれらに準じた
方法によつて下式のように製造できる。 〔式中、Ｘはハロゲン（例、塩素、臭素、ヨウ
素）を示し、その他の記号は前記と同意義〕 以下に実施例によつて本発明をさらに具体的に
示すが、本発明の範囲がこれらに限定されるもの
ではない。 実施例 キノン化合物（ａ−１〜ａ−47）およびヒ
ドロキノン化合物（ｂ−１〜ｂ−４）の製
造 Ａ法：Ｎ・N′−ジシクロヘキシルカルボジイミ
ド（DCC）とＮ−ヒドロキシサクシンイミド
を用いるアミド化 カルボン酸（ａまたはｂ；１〜10ｍmol）
を塩化メチレン（５〜50ml）に溶かし、Ｎ−ヒド
ロキシサクシンイミド（１〜10ｍmol×1.1）を加
えて氷冷する。これに撹拌下Ｎ・N′−ジシクロ
ヘキシルカルボジイミド（DCC、１〜10ｍmol×
1.1）を加え０℃で15分、さらに室温で２時間反
応し、この混合物にアミノ化合物（、１〜10ｍ
mol×1.1）を加えて同条件下に１〜３時間反応を
行う。反応終了後、Ｎ・N′−ジシクロヘキシル
尿素を別し、液を水洗、乾燥（硫酸マグネシ
ウム）後、溶媒を留去して、残渣をシリカゲルク
ロマトグラフイーに付し、イソプロピルエーテ
ル：酢酸エチル系の混合溶媒を用いて展開すると
目的とするキノン化合物（ａ）またはヒドロキ
ノン化合物（ｂ）が得られる。 Ｂ法：１−ヒドロキシベンゾトリアゾールと
DCCを用いるアミド化 カルボン酸（ａ；１〜10ｍmol）、１−ヒド
ロキシベンゾトリアゾール（１〜10ｍmol×1.1）
を塩化メチレン（５〜50ml）に溶かし、氷冷撹拌
する。これにDCC（１〜10ｍmol×1.1）を加
え、10分後アミノ化合物（、１〜10ｍmol×
1.1）を加える。氷冷下に１時間反応を行い、つ
いで室温で１〜３時間反応を行う。析出する結晶
を別し、液を水洗、乾燥（硫酸マグネシウ
ム）、濃縮し、残渣をシリカゲルクロマトグラフ
イーに付し、イソプロピルエーテル：酢酸エチル
系混合溶媒で展開し、目的の分画部を集めて濃縮
すると目的とするキノン化合物（ａ）が得られ
る。 Ｃ法：２−チアゾリン−２−チオールとCDDを
用いるアミド化 カルボン酸（ａ；１〜10ｍmol）を塩化メチ
レン（５〜50ml）に溶かし、２−チアゾリン−２
−チオール（１〜10ｍmol×1.1）とDCC（１〜
10ｍmol×1.1）を加え室温で20〜30分間反応し、
この混合物にアミノ化合物（、１〜10ｍmol×
1.1）を加え同反応条件下に１〜３時間反応を行
う。反応終了後、析出する結晶を別し、液を
水洗、乾燥（硫酸マグネシウム）、濃縮し、残渣
をシリカゲルクロマトグラフイーに付し、イソプ
ロピルエーテル：酢酸エチル系混合溶媒で展開
し、目的の分画部を集めて濃縮すると目的とする
キノン化合物（ａ）が得られる。 Ｄ法Ｎ−ヒドロキシ−５−ノルボルネン−２・３
−ジカルボキシイミド（HONB）とDCCを用
いるアミド化 カルボン酸（ａ；１〜10ｍmol）、HONB
（１〜10ｍmol×1.1）をジメチルホルムアミド
（DMF、５〜50ml）に溶解し、氷冷撹拌する。こ
れにDCCを加え10分。ついで氷浴をはずし、室
温で５時間撹拌。これにシトシンアラビノシツド
の溶液（DMF：水＝４：１、５〜50ml）を加
え、ついで80℃で５時間反応を行う。反応終了
後、溶媒を減圧留去し、残渣に酢酸エチルを加え
る。不溶物を別し、液を濃縮後、残渣をシリ
カゲルクロマトグラフイーに付し、酢酸エチル：
メタノール系溶媒で展開し、目的化合物を含む分
画部を集め、減圧乾固して、目的とするキノン化
合物（ａ）を得る。 Ｅ法：酸クロライドを経由するアミド化 カルボン酸（ａまたはｂ；１〜10ｍmol）
およびトリフエニルホスフイン（１〜10ｍmol×
1.1）を四塩化炭素（５〜50ml）に溶解し、30〜
40℃に加熱する。反応後反応液を氷冷し、これに
アミノ化合物（、１〜10ｍmol×1.1）と塩基
（例えばピリジン、１〜10ｍmol×1.1）を含む塩
化メチレン溶液を徐々に加える。滴加後、室温に
もどして10〜20分間反応を行う。反応溶液を水
洗、乾燥（硫酸マグネシウム）、濃縮し、残渣を
シリカゲルクロマトグラフイーに付し、イソプロ
ピルエーテル：酢酸エチル系溶媒で展開し、目的
の画部を濃縮して目的とするキノン化合物（
ａ）またはヒドロキノン化合物（ｂ）を得る。 Ｆ法：メトキシメチル基の除去とヒドロキノン体
の酸化 ヒドロキノン化合物（ｂ、R1＝CH3O、R2＝
−NHCH（CH3）2、R3＝−CH2OCH3、ｎ＝２、
2.54ｇ、5.0ｍmol）を１・２−ジメトキシエタン
（DME、30ml）に溶解し、２規定硫酸（5.0ml）
を加え70℃で１時間撹拌、冷却後、１モル塩化第
二鉄（10ml）を加え室温で反応。30分後、DME
を減圧留去し、残渣に酢酸エチル（50ml）、水
（10ml）を加え抽出。酢酸エチル層を水洗、乾燥
（硫酸マグネシウム）、濃縮して、残渣をイソプロ
ピルエーテルより再結晶すると目的とするキノン
化合物〔ａ、R1＝OCH3、R2＝NHCH
（CH3）2、Ｎ＝２、1.5ｇ〕、m.p.88−89℃が得ら
れる。 Ｇ法：酸化的脱メチル化反応によるキノン化合物
の製造 ヒドロキノン化合物（ｂ、 The present invention relates to a novel quinone compound useful as a pharmaceutical or an intermediate thereof, and a method for producing the same. Fat-soluble vitamins such as vitamin E, vitamin K, and ubiquinone generally exhibit vitamin or vitamin-like effects specific to each compound group in biological membranes, particularly in the phospholipid layer. The present inventors have discovered that a group of compounds in which the terminals of the polyprenyl side chains of these compounds are amidated have excellent physiological activity, and based on this, the present invention has been completed. That is, the compounds of the present invention have the general formula [In the formula, n is an integer from 1 to 10, R 1 is a methyl group, a methoxy group, or two R 1s -CH=CH-
CH=CH- group, R 2 is (1) amino, (2) mono- or di-C 1-6 alkylamino, (3) phenyl-C 1-3 alkylamino, (4) pyridyl-C 1-3 Alkylamino, (5) C 1-4 alkoxyamino, (6) hydroxyanilino, (7) m-trifluoromethylphenylhydrazino, (8) N・N-dimethylhydrazino, (9) histamino, ( 10) 4-Methyl-1-piperazinylamino, (11)
1-Methyl-4-piperidinylamino, (12)5-
(1H-tetrazolyl)amino, (13) pyrrolidinyl, (14) piperazinyl substituted with prenyl, polyprenyl, trimethoxybenzyl or methylenedioxybenzyl, (15) piperidino, (16)
morpholino or (17) represents an amino residue of epinephrine, norepinephrine, glycine, phenylglycine, methionine or β-cytosine arabinoside] and its hydroquinone form. The hydroquinone form of the above quinone compound (a) has the general formula [In the formula, n, R 1 and R 2 have the same meanings as above, and R 3 represents a hydrogen atom or a protective group]. Regarding (a) and (b) above, examples of the mono- or di-C 1-6 alkylamino group represented by R 2 include methylamino, ethylamino, propylamino, isopropylamino, butylamino,
isobutylamino, sec-butylamino, tert-
Butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, methylethylamino groups, etc.; phenyl-C 1-3 alkylamino groups include benzylamino, phenethylamino, α-methylbenzylamino groups, etc.; pyridyl-C Examples of 1-3 alkylamino groups include 2-pyridylmethylamino, 3-pyridylmethylamino, and 4-pyridylethylamino groups, and examples of C 1-4 alkoxyamino groups include methoxyamino and ethoxyamino groups. Or, examples of piperazinyl substituted with a polyprenyl group include prenylpiperazinyl, geranylpiperazinyl, farnesylpiperazinyl,
nerylpiperazinil, solanesylpiperazinil,
Examples of piperazinyl substituted with trimethoxybenzyl include 4-(3,4,5-trimethoxybenzyl)piperazinyl, and examples of piperazinyl substituted with methylenedioxybenzyl include geranylgeranylpiperazinyl. -(3,4-methylenedioxybenzyl)piperazinyl and the like.
The amino residue of epinephrine, norepinephrine, glycine, methionine or β-cytosine arabinoside represented by R 2 means a group with one hydrogen bonded to these amino groups removed. Regarding the above formula (b), the protecting group represented by R 3 includes a group usually used for protecting a hydroxyl group, such as a C 1-3 alkyl group (e.g., methyl group), a C 1-3 alkoxymethyl group (e.g., methoxy methyl group), C 2-4
Examples include an alkanoyl group (eg, acetyl group), a benzyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group, and the like. Compounds (a) and (b) of the present invention are, for example, represented by the general formula or [In the formula, n is an integer from 1 to 10, R 1 is a methyl group, a methoxy group, or two R 1s -CH=CH-
CH=CH- group, R 3 is a protecting group] or a reactive derivative of its carboxyl group is substituted with the general formula R 2 -H () [wherein R 2 is substituted or It can be produced by reacting and amidating a compound represented by the following formula which shows a good amino group. The reaction between carboxylic acid (a) or (b) and compound () is usually carried out in the presence of a suitable active condensing agent, such as N.N'-
Dicyclohexylcarbodiimide (DCC), N-
Hydroxybenzotriazole and DCC, N-hydroxysuccinimide and DCC, 2-thiazoline-2-thiol and DCC, p-nitrophenol and DCC, chlorocarbonate and triethylamine, etc. are used. The amount of condensing agent used is usually about 1 to 2 equivalents based on (a) or (b). The reaction is usually carried out in a suitable organic solvent (e.g. dichloromethane, tetrahydrofuran, acetonitrile, dimethylacetamide, dimethylformamide,
1,2-dimethoxyethane), approx. -20°C to 150°C
The reaction temperature is approximately ℃. Examples of the reactive derivatives of carboxylic acid (a) or (b) include acid chlorides, mixed acid anhydrides, active esters, and active amides, which can be prepared by methods known per se. ) or (b) as phosphorus pentachloride, oxalic acid chloride, thionyl chloride,
It can be obtained by reaction with carbon tetrachloride-triphenylphosphine, phosgene, etc. The amidation reaction is performed under commonly used synthetic reaction conditions, such as the presence of an organic base (e.g., triethylamine, pyridine, etc.) or an inorganic base (e.g., sodium carbonate, potassium carbonate, etc.).
Alternatively, it is carried out by reacting (b) and (). The quinone compound (a) and its hydroquinone (b) thus produced can be separated and purified by known separation and purification means (e.g., chromatography, crystallization).
It can be isolated and collected by such methods. In addition,
(a) and (b) can be interconverted by reactions known per se. For example, to lead protected (b) to (a), (b) is subjected to a known protecting group removal reaction (e.g., acidic hydrolysis, alkaline hydrolysis, etc.), followed by an oxidation reaction (e.g., air oxidation, chlorination, etc.). (ferric oxidation) or by subjecting (b) to an oxidative demethylation reaction (e.g., reaction with silver oxide), and vice versa, (a) to (b) can be reduced (e.g., by hydrogen Reduction with sodium boronate or sodium thiosulfate) and, if necessary, a protecting group introduction reaction (eg, etherification, benzylation, acylation) can achieve the respective objectives. Compounds (a) and (b) may form acid addition salts when a basic nitrogen functional group derived from, for example, a piperazine or pyridine skeleton is present in the R 2 group; Examples include salts of organic acids (eg, acetic acid, malonic acid, fumaric acid, maleic acid, succinic acid, oxalic acid, citric acid, tartaric acid) and salts of inorganic acids (eg, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid). In addition, when a carboxyl group derived from an amino acid is present in the R 2 group of (a) and (b), an alkali metal (e.g., lithium,
(sodium, potassium) salts may be formed. Naturally, these salts are also included within the scope of the compounds of the present invention. Compounds (a) and (b) of the present invention have regulatory effects on prostaglandin biosynthesis (enhancement of prostaglandin E 2 and I 2 effects, etc.), anti-SRS-A (slow
It has antihypertensive, analgesic, antiulcer, antiinflammatory, and diuretic effects on animals, especially mammals (e.g., rats, mice, guinea pigs, dogs, rabbits, and humans). , exhibits physiological effects such as immunomodulation, anti-asthma, anti-allergy, inhibiting platelet aggregation, and improving cerebral circulation, such as antihypertensive agents, analgesics, anti-ulcer agents, anti-inflammatory agents, diuretics, immunomodulators, and anti-asthmatic agents. , antiallergic agents, antithrombotic agents, cerebral circulation improving agents, etc., for example, for hypertension, cerebral thrombosis,
It is useful for the treatment or prevention of ischemic myocardial infarction, coronary vascular disorders, prostaglandin and thromboxane biosynthesis regulatory mechanism disorders, immunodeficiency, bronchial asthma, allergic diseases, and the like. The compounds of the present invention have low toxicity and can be used as is or in pharmaceutical compositions mixed with known pharmaceutically acceptable carriers, excipients, etc. [e.g., tablets, capsules (including soft capsules and microcapsules), liquid preparations, injections] It can be safely administered orally or parenterally as a drug or suppository. The dosage varies depending on the subject, administration route, symptoms, etc., but for example, when orally administered to adults with hypertension or bronchial asthma, a single dose is usually about
0.2mg/Kg to 25mg/Kg body weight, preferably about 0.5
It is convenient to administer about 10 mg/Kg body weight about 1 to 3 times a day. Compounds (a) and (b) used as raw material compounds in the method of the present invention are disclosed, for example, in JP-A-53-50123, JP-A-54-76507, JP-A-55-153739, The Journal. ·off·
Organic Chemistry (The Journal of
Organic Chemistry), Volume 44, Page 868 (1979)
and synthesis, p. 467 (1979)
It can be manufactured as shown in the following formula using the method described in 2010) or a method similar thereto. [wherein, It is not limited to these. Example Production of quinone compounds (a-1 to a-47) and hydroquinone compounds (b-1 to b-4) Method A: Amidation using N·N'-dicyclohexylcarbodiimide (DCC) and N-hydroxysuccinimide Carboxylic acid (a or b; 1-10 mmol)
Dissolve in methylene chloride (5-50 ml), add N-hydroxysuccinimide (1-10 mmol x 1.1) and cool on ice. To this was added N・N′-dicyclohexylcarbodiimide (DCC, 1 to 10 mmol ×
1.1) and reacted at 0°C for 15 minutes and then at room temperature for 2 hours.
mol x 1.1) and react under the same conditions for 1 to 3 hours. After the reaction was completed, N·N'-dicyclohexylurea was separated, the liquid was washed with water, dried (magnesium sulfate), the solvent was distilled off, and the residue was subjected to silica gel chromatography to obtain an isopropyl ether:ethyl acetate system. When developed using a mixed solvent, the desired quinone compound (a) or hydroquinone compound (b) is obtained. Method B: 1-hydroxybenzotriazole and
Amidation using DCC Carboxylic acid (a; 1-10 mmol), 1-hydroxybenzotriazole (1-10 mmol x 1.1)
Dissolve in methylene chloride (5-50 ml) and stir under ice cooling. DCC (1-10 mmol x 1.1) was added to this, and after 10 minutes the amino compound (1-10 mmol x
Add 1.1). The reaction is carried out under ice cooling for 1 hour, and then at room temperature for 1 to 3 hours. Separate the precipitated crystals, wash the liquid with water, dry (magnesium sulfate), and concentrate. The residue is subjected to silica gel chromatography, developed with a mixed solvent of isopropyl ether and ethyl acetate, and the desired fractions are collected. When concentrated, the desired quinone compound (a) is obtained. Method C: Amidation using 2-thiazoline-2-thiol and CDD Dissolve carboxylic acid (a; 1-10 mmol) in methylene chloride (5-50 ml),
-thiol (1~10 mmol x 1.1) and DCC (1~10 mmol x 1.1)
Add 10 mmol x 1.1) and react at room temperature for 20 to 30 minutes.
Add the amino compound (1 to 10 mmol×
Add 1.1) and react for 1 to 3 hours under the same reaction conditions. After the reaction is complete, the precipitated crystals are separated, the liquid is washed with water, dried (magnesium sulfate), concentrated, and the residue is subjected to silica gel chromatography, developed with a mixed solvent of isopropyl ether and ethyl acetate to obtain the desired fraction. The desired quinone compound (a) is obtained by collecting and concentrating the portions. Method D N-hydroxy-5-norbornene-2.3
- Amidation using dicarboximide (HONB) and DCC Carboxylic acid (a; 1-10 mmol), HONB
(1-10 mmol x 1.1) is dissolved in dimethylformamide (DMF, 5-50 ml) and stirred under ice cooling. Add DCC to this and leave for 10 minutes. Then, remove the ice bath and stir at room temperature for 5 hours. A solution of cytosine arabinoside (DMF:water = 4:1, 5-50ml) is added to this, and the reaction is then carried out at 80°C for 5 hours. After the reaction is complete, the solvent is distilled off under reduced pressure, and ethyl acetate is added to the residue. After separating the insoluble matter and concentrating the liquid, the residue was subjected to silica gel chromatography and ethyl acetate:
It is developed with a methanol-based solvent, and fractions containing the target compound are collected and dried under reduced pressure to obtain the target quinone compound (a). Method E: Amidation via acid chloride Carboxylic acid (a or b; 1-10 mmol)
and triphenylphosphine (1-10 mmol×
Dissolve 1.1) in carbon tetrachloride (5~50ml) and add 30~
Heat to 40°C. After the reaction, the reaction solution is cooled on ice, and a methylene chloride solution containing an amino compound (1 to 10 mmol x 1.1) and a base (for example, pyridine, 1 to 10 mmol x 1.1) is gradually added thereto. After the dropwise addition, the temperature is returned to room temperature and the reaction is carried out for 10 to 20 minutes. The reaction solution was washed with water, dried (magnesium sulfate), and concentrated, and the residue was subjected to silica gel chromatography, developed with isopropyl ether:ethyl acetate, and the desired fraction was concentrated to obtain the desired quinone compound (
a) or hydroquinone compound (b) is obtained. Method F: Removal of methoxymethyl group and oxidation of hydroquinone compound Hydroquinone compound (b, R 1 = CH 3 O, R 2 =
-NHCH( CH3 ) 2 , R3 = -CH2OCH3 , n=2,
2.54g, 5.0mmol) was dissolved in 1,2-dimethoxyethane (DME, 30ml), and 2N sulfuric acid (5.0ml) was added.
The mixture was stirred at 70°C for 1 hour, and after cooling, 1M ferric chloride (10ml) was added and reacted at room temperature. After 30 minutes, DME
was distilled off under reduced pressure, and the residue was extracted with ethyl acetate (50 ml) and water (10 ml). The ethyl acetate layer is washed with water, dried (magnesium sulfate), and concentrated, and the residue is recrystallized from isopropyl ether to obtain the desired quinone compound [a, R 1 = OCH 3 , R 2 = NHCH
(CH 3 ) 2 , N=2, 1.5 g], mp 88-89°C. G method: Production of quinone compound by oxidative demethylation reaction Hydroquinone compound (b,

【式】 R2＝NH2、R3＝CH3、ｎ＝３、4.63ｇ、10ｍ
mol）をジオキサン（56ml）に溶かし酸化銀
（AgO、4.96ｇ、40ｍmol）を加え、撹拌下に室
温で６規定硝酸（20ml）を加え30分間反応し、水
（150ml）を加えて、生成物を酢酸エチルで抽出す
る。有機層を水洗、乾燥（硫酸マグネシウム）、
濃縮後、残渣をシリカゲルカラムクロマトグラフ
イーに付し、酢酸エチルで展開し、濃縮後、生成
物を酢酸エチルで結晶化すると目的のキノン化合
物（ａ、[Formula] R 2 = NH 2 , R 3 = CH 3 , n = 3, 4.63g, 10m
Dissolve silver oxide (AgO, 4.96 g, 40 mmol) in dioxane (56 ml), add 6N nitric acid (20 ml) at room temperature with stirring, react for 30 minutes, add water (150 ml), and dissolve the product. is extracted with ethyl acetate. Wash the organic layer with water, dry (magnesium sulfate),
After concentration, the residue was subjected to silica gel column chromatography and developed with ethyl acetate. After concentration, the product was crystallized from ethyl acetate to obtain the desired quinone compound (a,

【式】R2＝NH2、ｎ＝３、 3.35ｇ）、mp90−91℃が得られる。 上記Ａ−Ｇ法により製造された化合物およびそ
れらの物性を以下の表に示す。[Formula] R 2 = NH 2 , n = 3, 3.35 g), mp 90-91°C is obtained. The compounds produced by the above A-G method and their physical properties are shown in the table below.

【表】【table】

【表】【table】

【表】【table】

【表】【table】

【表】【table】

【表】【table】

【表】【table】

【表】【table】

【表】【table】

【表】【table】

【表】【table】

【表】【table】

【表】【table】

【表】【table】

【表】【table】

【表】【table】

【表】【table】

【表】 実施例 キノン化合物（ａ、R1＝OCH3、ｎ＝２、
376mg）を塩化メチレン（５ml）に溶解し、これ
にDCC（210mg）とトリエチルアミン（100mg）
を加えて室温で１時間撹拌。反応後、有機層を水
洗、乾燥硫酸マグネシウム）、濃縮し、残渣をイ
ソプロピルエーテルから結晶化すると目的とする
キノン化合物（ａ、R1＝OCH3、
[Table] Example Quinone compound (a, R 1 = OCH 3 , n = 2,
376 mg) was dissolved in methylene chloride (5 ml), and DCC (210 mg) and triethylamine (100 mg) were dissolved in methylene chloride (5 ml).
and stirred at room temperature for 1 hour. After the reaction, the organic layer is washed with water, dried magnesium sulfate) and concentrated, and the residue is crystallized from isopropyl ether to obtain the desired quinone compound (a, R 1 = OCH 3 ,

【式】ｎ＝２、520mg）、 mp113−115℃が得られる。C34H50N2O6（MW：
582.76）。[Formula] n=2, 520 mg), mp113-115°C is obtained. C 34 H 50 N 2 O 6 (MW:
582.76).

Claims (1)

【特許請求の範囲】 １ 一般式 ［式中、ｎは１から10までの整数を、R1はメチル
基、メトキシ基または２つのR1で−CH＝CH−
CH＝CH−基を示し、R2は(1)アミノ、(2)モノま
たはジC1-6アルキルアミノ、(3)フエニル−C1-3ア
ルキルアミノ、(4)ピリジル−C1-3アルキルアミ
ノ、(5)C1-4アルコキシアミノ、(6)ヒドロキシアニ
リノ、(7)ｍ−トリフロロメチルフエニルヒドラジ
ノ、(8)Ｎ・Ｎ−ジメチルヒドラジノ、(9)ヒスタミ
ノ、(10)４−メチル−１−ピペラジニルアミノ、(11)
１−メチル−４−ピペリジニルアミノ、(12)５−
（1H−テトラゾリル）アミノ、（13）ピロリジニ
ル、（14）プレニル、ポリプレニル、トリメトキ
シベンジルまたはメチレンジオキシベンジルで置
換されたピペラジニル、（15）ピペリジノ、（16）
モルホリノまたは（17）エピネフリン、ノルエピ
ネフリン、グリシン、フエニルグリシン、メチオ
ニンまたはβ−シトシンアラビノサイドのアミノ
残基を示す］で表わされるキノン化合物またはそ
のヒドロキノン体。[Claims] 1. General formula [In the formula, n is an integer from 1 to 10, R 1 is a methyl group, a methoxy group, or two R 1s -CH=CH-
CH=CH- group, R 2 is (1) amino, (2) mono- or di-C 1-6 alkylamino, (3) phenyl-C 1-3 alkylamino, (4) pyridyl-C 1-3 Alkylamino, (5) C 1-4 alkoxyamino, (6) hydroxyanilino, (7) m-trifluoromethylphenylhydrazino, (8) N・N-dimethylhydrazino, (9) histamino, ( 10) 4-Methyl-1-piperazinylamino, (11)
1-Methyl-4-piperidinylamino, (12)5-
(1H-tetrazolyl)amino, (13) pyrrolidinyl, (14) piperazinyl substituted with prenyl, polyprenyl, trimethoxybenzyl or methylenedioxybenzyl, (15) piperidino, (16)
A quinone compound represented by morpholino or (17) representing an amino residue of epinephrine, norepinephrine, glycine, phenylglycine, methionine or β-cytosine arabinoside, or a hydroquinone thereof.
JP11777179A 1979-05-18 1979-09-12 Quinone compound and its preparation Granted JPS5640651A (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP11777179A JPS5640651A (en) 1979-09-12 1979-09-12 Quinone compound and its preparation
US06/182,401 US4388312A (en) 1979-09-12 1980-08-26 Quinone derivatives, their production and use
DE8080303172T DE3061226D1 (en) 1979-09-12 1980-09-10 Quinone derivatives, their production and use
EP80303172A EP0025692B1 (en) 1979-09-12 1980-09-10 Quinone derivatives, their production and use
CA000360089A CA1173028A (en) 1979-08-12 1980-09-11 Quinone derivatives, their production and use
US06/471,457 US4533554A (en) 1979-05-18 1983-03-02 Quinone derivatives and use

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP11777179A JPS5640651A (en) 1979-09-12 1979-09-12 Quinone compound and its preparation

Publications (2)

Publication Number Publication Date
JPS5640651A JPS5640651A (en) 1981-04-16
JPS6247176B2 true JPS6247176B2 (en) 1987-10-06

Family

ID=14719910

Family Applications (1)

Application Number Title Priority Date Filing Date
JP11777179A Granted JPS5640651A (en) 1979-05-18 1979-09-12 Quinone compound and its preparation

Country Status (5)

Country Link
US (1) US4388312A (en)
EP (1) EP0025692B1 (en)
JP (1) JPS5640651A (en)
CA (1) CA1173028A (en)
DE (1) DE3061226D1 (en)

Families Citing this family (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1247632A (en) * 1981-06-19 1988-12-28 Frederick H. Howell Hydroquinones
JPS58177934A (en) * 1982-04-13 1983-10-18 Takeda Chem Ind Ltd Benzoquinone derivative
US4808339A (en) * 1982-04-13 1989-02-28 Takeda Chemical Industries, Ltd. Benzoquinone derivatives
EP0098241B1 (en) * 1982-06-16 1985-10-02 Ciba-Geigy Ag Hydroquinone ethers and a process for preparing them
CH661516A5 (en) * 1983-12-08 1987-07-31 Hoffmann La Roche PHENYLNONATETRAENOYL SUGAR DERIVATIVES.
US4737519A (en) * 1983-12-14 1988-04-12 The Upjohn Company Substituted naphthalenes, indoles, benzofurans, and benzothiophenes as lipoxygenase inhibitors
US4849445A (en) * 1983-12-14 1989-07-18 The Upjohn Company Method for treating or preventing deep vein thrombosis using lipoxygenase inhibitors
US4791138A (en) * 1983-12-14 1988-12-13 The Upjohn Company Method for treating or preventing deep vein thrombosis using lipoxygenase inhibitors
JPS6122054A (en) * 1984-05-09 1986-01-30 Eisai Co Ltd Polyprenyl compound
JPS60255749A (en) * 1984-05-31 1985-12-17 Univ Nagoya Quinone derivative
JPH0610177B2 (en) * 1985-05-08 1994-02-09 エーザイ株式会社 Quinone compound
US4617311A (en) * 1985-05-17 1986-10-14 Eli Lilly And Company Antiasthmatic method
US4939169A (en) * 1985-09-20 1990-07-03 The Upjohn Company 1,4-naphthalenediol and 1,4-hydroquinone derivatives
US4851586A (en) * 1985-09-20 1989-07-25 The Upjohn Company 1,4-naphthalenediol and 1,4-hydroquinone derivatives
US4686220A (en) * 1985-12-19 1987-08-11 American Cyanamid Company Substituted 2-[b-substituted-amino)-ethylamino]-1,4-naphthalenediones for treating asthma, allergic diseases and inflammation in warm-blooded animals
DE3768516D1 (en) * 1986-01-28 1991-04-18 Takeda Chemical Industries Ltd CHINONAMIDES, THEIR PRODUCTION AND USE.
DE3767527D1 (en) * 1986-03-29 1991-02-28 Suntory Ltd DERIVATIVES OF BENZOQUINONYLPHENYL ALKANIC ACID AMID.
JPH062755B2 (en) * 1987-07-09 1994-01-12 サントリー株式会社 Hydroquinonylphenyl butyric acid amide derivative
ATE173022T1 (en) * 1991-08-08 1998-11-15 Amylin Pharmaceuticals Inc PRODUCTION OF PEPTIDE AMIDES
DK1888059T3 (en) 2005-06-01 2015-03-30 Edison Pharmaceuticals Inc Redox-active therapeutic products for the treatment of mitochondrial diseases and other conditions as well as modulation of energy biomarkers
PL1933821T3 (en) * 2005-09-15 2021-01-11 Ptc Therapeutics, Inc. Tail variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers
EP1986636B1 (en) 2006-02-22 2013-04-24 Edison Pharmaceuticals, Inc. Phenol and 1,4-benzoquinone derivatives for use in the treatment of mitochondrial diseases
EP3018122B1 (en) 2007-11-06 2018-10-10 BioElectron Technology Corporation 4-(p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases
JP5710277B2 (en) * 2008-03-05 2015-04-30 エジソン ファーマシューティカルズ， インコーポレイテッド 2-Substituted-p-quinone derivatives for the treatment of oxidative stress diseases
EP2344142B1 (en) 2008-09-10 2024-06-26 PTC Therapeutics, Inc. Treatment of pervasive developmental disorders with redox-active therapeutics
US8263094B2 (en) * 2008-09-23 2012-09-11 Eastman Chemical Company Esters of 4,5-disubstituted-oxy-2-methyl-3,6-dioxo-cyclohexa-1,4-dienyl alkyl acids and preparation thereof
GB0817528D0 (en) 2008-09-24 2008-10-29 Syntavit As Process
GB2476643B (en) * 2009-12-23 2012-11-14 Haomamedica Ltd 1,4-Dihydro-1,4-dioxonaphtalene derivatives as anticoagulants
GB2476644B (en) * 2009-12-23 2012-11-14 Haomamedica Ltd 1,4-Dihydro-1,4-dioxonaphtalene derivatives for the treatment of osteoporosis
US9193700B2 (en) * 2011-05-26 2015-11-24 Indiana University Research And Technology Corporation Quinone compounds for treating Ape1 mediated diseases
WO2012167122A1 (en) 2011-06-03 2012-12-06 Indiana University Research And Technology Corporation Compounds, compositions and methods for treating oxidative dna damage disorders
WO2014039917A1 (en) 2012-09-07 2014-03-13 Edison Pharmaceuticals, Inc. Benzoquinone derivatives for treating oxidative stress disorders
CA2912871A1 (en) * 2013-05-31 2014-12-04 Edison Pharmaceuticals, Inc. Carboxylic acid derivatives for treatment of oxidative stress disorders
EP3233786B1 (en) 2014-12-16 2022-03-16 PTC Therapeutics, Inc. Polymorphic and amorphous forms of (r)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide
US10703701B2 (en) 2015-12-17 2020-07-07 Ptc Therapeutics, Inc. Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders
US10934253B2 (en) 2017-04-21 2021-03-02 University Of Tasmania Therapeutic compounds and methods

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3562277A (en) * 1967-09-06 1971-02-09 Shulton Inc Ketonic derivatives of phenyl piperazines
US3950418A (en) * 1970-02-02 1976-04-13 Hoffmann-La Roche Inc. Vitamin A acid amides
US3728362A (en) * 1970-02-07 1973-04-17 Takeda Chemical Industries Ltd (3-methyl-5-carboxy-2-pentenyl)quinones
US3879448A (en) * 1970-02-07 1975-04-22 Takeda Chemical Industries Ltd 4-hexenoic compounds
DE2104871A1 (en) * 1970-02-07 1971-08-26
US3875163A (en) * 1972-02-29 1975-04-01 Pierrel Spa Nitrogen containing acyclic isoprenoid compounds
DE2431198C2 (en) * 1973-07-02 1987-04-30 Takeda Chemical Industries, Ltd., Osaka Quinone derivatives and pharmaceutical preparations containing them
CH585709A5 (en) * 1973-08-24 1977-03-15 Hoffmann La Roche
JPS5919930B2 (en) * 1974-05-02 1984-05-09 武田薬品工業株式会社 Method for producing quinonic acid derivatives
US4090942A (en) * 1976-05-19 1978-05-23 Gulf Research & Development Company Process for producing benzene

Also Published As

Publication number Publication date
CA1173028A (en) 1984-08-21
DE3061226D1 (en) 1983-01-05
JPS5640651A (en) 1981-04-16
US4388312A (en) 1983-06-14
EP0025692B1 (en) 1982-12-01
EP0025692A1 (en) 1981-03-25

Similar Documents

Publication Publication Date Title
JPS6247176B2 (en)
CH660738A5 (en) VINYL-6 FURO- (3,4-C) -PYRIDINE DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS BASED ON SUCH COMPOUNDS.
JPH03505335A (en) Novel sulfonamides derived from benzocyclic or benzoheterocyclic acids, their production methods and their pharmaceutical uses
JPS62149662A (en) N-containing heterocyclic compound
KR20070038496A (en) Factor viia inhibitor
JPH0150698B2 (en)
US4404214A (en) 2-Pyridinecarboxamide derivatives compositions containing same and method of using same
EP0447116B1 (en) Urea derivatives, their production, and pharmaceutical compositions containing them
JPH0559117B2 (en)
JPS63295539A (en) Substituted biphenyl derivative
JPS61100593A (en) Griseolic acid derivative
EP0059108A1 (en) Derivatives of dihydroxybenzoic acid
EP0152799B1 (en) Compounds having peripheral calcium antagonist, anticonvulsive and eumetabolic activity, processes for the preparation thereof and pharmaceutical compositions containing them
US4038413A (en) Treating iron deficiency anaemia
JPS62114946A (en) Phenylserinamide derivative and agent for central nervous system comprising same as active ingredient
US4624949A (en) Dibenzo[b,d]thiopyran derivatives, pharmaceutical composition and use
JPS63246378A (en) 8-azaxanthines, manufacture and medicinal composition
KR920001788B1 (en) A process for the preparation of a mixture of diastereoisomer compound as obtained from (-)-5-(1-hidroxy-1-methylethyl)-2-cyclohexene-1-one
JPS61268651A (en) Phenylacetic acid derivative and production thereof
US4017623A (en) Esters of 2-[(4-quinolyl)amino]-benzoic acids in analgesic and anti-inflammatory compositions
KR790001695B1 (en) Process for the preparation of benz cycloamide derivatives
JPS6024789B2 (en) 5-Fluorouracil derivative compound
JPS63216867A (en) Sugar lactam derivative and anti-inflammatory agent containing same
JPS60185766A (en) Novel azabicyclo compound and manufacture
JPS6145625B2 (en)